Cancer and Stress: Does It Make a Difference to the Patient When These Two Challenges Collide?

Abstract

A single head and neck Cancer (HNC) is a globally growing challenge associated with significant morbidity and mortality. The diagnosis itself can affect the patients profoundly let alone the complex and disfiguring treatment. The highly important functions of structures of the head and neck such as mastication, speech, aesthetics, identity and social interactions make a cancer diagnosis in this region even more psychologically traumatic. The emotional distress engendered as a result of functional and social disruption is certain to negatively affect health-related quality of life (HRQoL). The key biological responses to stressful events are moderated through the combined action of two systems, the hypothalamus-pituitary-adrenal axis (HPA) which releases glucocorticoids and the sympathetic nervous system (SNS) which releases catecholamines. In acute stress, these hormones help the body to regain homeostasis; however, in chronic stress their increased levels and activation of their receptors may aid in the progression of cancer. Despite ample evidence on the existence of stress in patients diagnosed with HNC, studies looking at the effect of stress on the progression of disease are scarce, compared to other cancers. This review summarises the challenges associated with HNC that make it stressful and describes how stress signalling aids in the progression of cancer. Growing evidence on the relationship between stress and HNC makes it paramount to focus future research towards a better understanding of stress and its effect on head and neck cancer.

Keywords: HNC; cancer; glucocorticoid signalling; stress; β-adrenergic signalling.

Figure 1

Summary of the challenges associated with head and neck cancers. The diagnosis itself, complex treatment plans, functional disability in terms of speech and mastication, concerns around body image that in turn lead to compromised social interactions, and fear of recurrence (FCR) are some of the challenges faced by the patients with head and neck cancers (HNC). These challenges decrease the quality of life (QoL) and increase psychological stress.

Figure 2

Response of the body to stress. A stressor (1), causes the central nervous system (CNS) (2), to activate the sympathetic nervous system (SNS) (3), and hypothalamus–pituitary–adrenal axis (HPA) (4). Sympathetic nervous system (SNS) activates adrenal medulla (5), which releases catecholamines (6). Hypothalamus releases corticotropin-releasing hormone (CRH) (7), which causes the pituitary gland to release adrenocorticotropic hormone (ACTH) (8). Adrenocorticotropic hormone (ACTH) results in the release of cortisone (9), from adrenal cortex. Cortisone is activated by the enzyme 11-β hydroxysteroid dehydrogenase type 1 (11-β HSD-1) to cortisol and 11-β hydroxysteroid dehydrogenase type 2 (11-β HSD-2) to cortisone, in the target organs (10).

Figure 3

Adrenergic signalling pathway and mechanisms. The binding of Epinephrine (E) and Norepinephrine (N) to β-adrenergic receptors (β-ADR) results in Gαs-mediated activation of adenylyl cyclase (1,2). This causes a transient influx of cyclic AMP (cAMP) (3). cAMP activates the two effector pathways, Protein Kinase A (PKA) and exchange protein directly activated by cyclic AMP (EPAC) (4). PKA phosphorylates Bcl-2 associated agonist of cell death (BAD) which makes the cells resistant to apoptosis and anoikis (5). It also phosphorylates β-adrenergic receptor kinase (BARK) which recruits β-arrestin, further phosphorylating Src and Focal Adhesion Kinase (FAK), resulting in cell motility (6). In cervical cancer cells, sustained adrenergic signalling that results in PKA activation causes inhibition of the tumour suppressive Hippo Yap pathway. PKA targets the tumour suppressor Neurofibromin 2 (NF-2), as a result of which the downstream phosphorylation of mammalian Ste20-like kinases ½ (MST1/2; homologs of Drososphila Hippo (Hpo)), large tumour suppressor ½ (LATS ½; homologs of Drosophila Warts (Wts)) and Yes-Associated Protein (YAP) is inhibited. The dephosphorylated YAP translocates into the nucleus and inhibits apoptosis (7). β-adrenergic receptors activated by stress lead to cAMP-PKA/AKT/mTOR/P70S6K/HIFα pathway-dependent proliferation and angiogenesis (8). EPAC leads to the activation of BRAF-MAPK signalling pathway (9). The transcription factors STAT3, CREB, ETS, AP1 are phosphorylated by PKA as well as by EPAC (10) which upregulate the expression of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, matrix metalloproteinases (MMPs), SNAI-2 involved in angiogenesis and invasion. Adapted from [91,94,96,100].

Figure 4

The human glucocorticoid receptor (hGR) gene. The hGR gene, called NR3C1 is located on chromosome 5 (5q31.32) and spans 160kb.

Figure 5

Glucocorticoid receptor α and β isoforms. Alternative splicing of the human glucocorticoid receptor gene (hGR) in exon 9, results in two receptor isoforms GRα and β, which differ at the ends of their C-termini by the number of amino acids in the ligand-binding domain (LBD). The three major domains of the hGR are N-terminal domain (NTD), DNA-binding domain (DBD) and ligand-binding domain (LBD). The N-terminal domain contains a major transactivation domain called Activation Factor-1 (AF-1), critical for the transcriptional activation of the receptor. DNA-binding domain (DBD) contains amino acids responsible for GR homodimerisation. The LBD consists of the ligand-binding site. GRα contains 50 additional amino acids in its ligand-binding domain (LBD) with a molecular weight of 97 kDa and GRβ contains 15 amino acids with a molecular weight of 94 kDa. Of the two isoforms, only GRα binds to the glucocorticoids. Adapted from [109].

Figure 6

Genomic and non-genomic glucocorticoid signalling. Hypothalamic–pituitary–adrenal axis (HPA) releases glucocorticoids (GC) in response to stress (1). GC binding to cytosolic glucocorticoid receptor (GR) results in the dissociation of heat shock proteins (Hsp 90, Hsp 40, Hsp 70) and brings a conformational change leading to the phosphorylation and dimerisation of GR. (2,3). The GC-GR complex translocates into the nucleus (4), where it may result in transcriptional upregulation by direct DNA binding to positive glucocorticoid response elements (GRE) and down-regulation by binding to negative glucocorticoid response elements (nGRE) (5) or indirect DNA binding via transcriptional factors (TF) (6). The rapidly occurring non genomic mechanisms take place through the membranous glucocorticoid receptor (mGR) (7) that activate the proliferative signalling pathways, and cause inhibition of apoptosis by translocation of GR to mitochondria (8). Adapted from [125].